Systems and methods for reducing or preventing backflow in a delivery system

ABSTRACT

Systems and methods are disclosed herein that generally involve CED devices with various features for reducing or preventing backflow. In some embodiments, CED devices include a tissue-receiving space disposed proximal to a distal fluid outlet. Tissue can be compressed into or pinched/pinned by the tissue-receiving space as the device is inserted into a target region of a patient, thereby forming a seal that reduces or prevents proximal backflow of fluid ejected from the outlet beyond the tissue-receiving space. In some embodiments, CED devices include a bullet-shaped nose proximal to a distal fluid outlet. The bullet-shaped nose forms a good seal with surrounding tissue and helps reduce or prevent backflow of infused fluid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/738,850 filed on Dec. 18, 2012 and U.S. Provisional Application No.61/835,912 filed on Jun. 17, 2013, which are each incorporated herein byreference in their entirety.

FIELD

The present invention relates to systems and methods for reducing orpreventing backflow in delivery systems, such as convection-enhanceddelivery systems for delivering therapeutic agents to a patient.

BACKGROUND

In convection-enhanced delivery (CED), drugs are infused locally intotissue through a needle, cannula, or microcatheter inserted into thetissue. Transport of the infused material is dominated by convection,which enhances drug penetration into the target tissue compared withdiffusion-mediated delivery or systemic delivery.

CED has emerged as a leading investigational delivery technique for thetreatment of several disorders. Clinical trials using existing devicesshow mixed results and suggest that the outcome of the therapy dependsstrongly on the extent of penetration and distribution of the drug intothe target tissue, which is determined by infusion velocity, therelative rates of convection and elimination during CED, and variousproperties of the target tissue.

As infusion velocity increases, there can be a tendency for the infusedfluid to flow back along the insertion pathway, between the exterior ofthe microcatheter and the surrounding tissue. Flexible microcatheterdesigns have been constructed to reduce this backflow of thedrug-containing fluid. However, fluid backflow during CED treatmentstill remains a critical problem in clinical practice. This isparticularly true in the case of CED within the brain, as theporoelastic nature of the brain tissue contributes to backflow orreflux. There is therefore a need for improved CED devices, e.g., CEDdevices that reduce or eliminate backflow of the infused fluid betweenthe exterior of the device and the surrounding tissue.

SUMMARY

Systems and methods are disclosed herein that generally involve CEDdevices with various features for reducing or preventing backflow. Insome embodiments, CED devices include a tissue-receiving space disposedproximal to a distal fluid outlet. Tissue can be compressed into orpinched/pinned by the tissue-receiving space as the device is insertedinto a target region of a patient, thereby forming a seal that reducesor prevents proximal backflow of fluid ejected from the outlet beyondthe tissue-receiving space. In some embodiments, CED devices include abullet-shaped nose proximal to a distal fluid outlet. The bullet-shapednose forms a good seal with surrounding tissue and helps reduce orprevent backflow of infused fluid.

In some embodiments, a convection-enhanced-delivery (CED) device isprovided that includes a micro-tip having a proximal portion, a centralportion, a distal portion, and at least one fluid channel extendingalong said proximal, central, and distal portions, the at least onefluid channel having an outlet port at a distal end thereof and an inletport at a proximal end thereof. The device also includes a first outersheath disposed coaxially over the distal portion of the micro-tip suchthat the distal portion of the micro-tip protrudes from a distal end ofthe first outer sheath, a first tissue-receiving space defined betweenan exterior surface of the micro-tip and an interior surface of thedistal end of the first outer sheath, and a catheter body extendingproximally from the micro-tip such that the at least one fluid channelof the micro-tip is in fluid communication with a respective inner lumenof the catheter body. The device also includes a nose portion disposedover at least the central portion of the micro-tip and extending betweenthe first outer sheath and the catheter body such that the nose portiondefines an exterior surface that tapers from a reduced distal diametercorresponding to the outside diameter of the first outer sheath to anenlarged proximal diameter corresponding to the outside diameter of thecatheter body.

The tissue-receiving space can be configured to compress tissue receivedtherein as the device is advanced through the tissue. Tissue compressedby the tissue-receiving space can form a seal that reduces proximalbackflow of fluid ejected from the outlet port of the at least one fluidchannel beyond the tissue-receiving space. The device can include asecond outer sheath disposed over the first outer sheath such that asecond tissue-receiving space is defined between an exterior surface ofthe first outer sheath and an interior surface of a distal end of thesecond outer sheath. The interior surface of the distal end of the firstouter sheath can be shaped to compress tissue received therein as thedevice is advanced through the tissue. The interior surface of thedistal end of the first outer sheath can be conical, convex, and/orconcave.

An inside diameter of the distal end of the first outer sheath can beabout 1 μm to about 200 μm greater than an outside diameter of thedistal portion of the micro-tip. An inside diameter of the distal end ofthe first outer sheath can be about 10 percent to about 100 percentgreater than an outside diameter of the distal portion of the micro-tip.The first outer sheath can have a circular outside cross-section. The atleast one fluid channel can be formed from at least one of a parylenecomposition, a silastic composition, a polyurethane composition, and aPTFE composition. The device can include a fluid reservoir in fluidcommunication with the inner lumen of the catheter body and configuredto supply a fluid thereto under positive pressure. The micro-tip can beflexible. The micro-tip can include an embedded microsensor.

The embedded microsensor can include at least one of an interrogatablesensor, a pressure sensor, a glutamate sensor, a pH sensor, atemperature sensor, an ion concentration sensor, a carbon dioxidesensor, an oxygen sensor, and a lactate sensor. The distal end of themicro-tip can have an atraumatic shape configured to penetrate tissuewithout causing trauma. The micro-tip can contain a quantity of a drug,can be coated with a drug, and/or can be impregnated with a drug. Thedrug can include at least one of an antibacterial agent, ananti-inflammatory agent, a corticosteroid, and dexamethasone. Themicro-tip can include a substrate having the at least one fluid channelformed thereon. The substrate can have a rectangular transversecross-section. The catheter body can be formed from a rigid material.Each inner lumen of the catheter body can be defined by a sleeve formedfrom a flexible material. The catheter body can be formed from at leastone of ceramic, PEEK, and polyurethane. Each sleeve can be formed fromat least one of polyimide, pebax, PEEK, polyurethane, silicone, andfused silica. The catheter body can be formed from a flexible material.The device can be assembled by forming the nose portion by molding thenose portion over the first outer sheath, inserting the micro-tip into aproximal end of the nose portion, coupling the proximal portion of themicro-tip to the catheter body, and injecting a flowable materialthrough an inlet port formed in the nose portion to fill the interior ofthe nose portion and secure the micro-tip and catheter body to the noseportion.

In some embodiments, a convection-enhanced-delivery (CED) device isprovided that includes a fluid conduit having proximal and distal ends,a first outer sheath disposed coaxially over the fluid conduit such thatthe fluid conduit extends out of a distal end of the first outer sheath,and a first tissue-receiving space defined between an exterior surfaceof the fluid conduit and an interior surface of the distal end of thefirst outer sheath.

In some embodiments, a micro-molding device is provided that includes amold cavity sized and configured to receive a catheter body and acatheter micro-tip therein such that at least one fluid channel of themicro-tip is at least partially disposed within a corresponding fluidline of the catheter body. The device also includes one or more moldchannels though which a mold fluid can be injected to fill the moldcavity and secure the micro-tip to the catheter body such that the atleast one fluid channel of the micro-tip is in fluid communication withthe at least one fluid line of the catheter body. The device can betransparent to allow UV light to pass therethrough to cure mold fluiddisposed within the mold cavity. The mold cavity can be sized andconfigured to form a bullet nose portion over the micro-tip and over atleast a portion of an outer sheath received in the mold cavity.

In some embodiments, a method of delivering a therapeutic agent to apatient is provided. The method includes advancing a fluid conduithaving a first outer sheath disposed therearound into tissue to compresstissue into a first tissue-receiving space defined between an exteriorsurface of the fluid conduit and an interior surface of the distal endof the first outer sheath. The method also includes delivering fluidcontaining the therapeutic agent under positive pressure through thefluid conduit and into a portion of the tissue adjacent to a distal endof the fluid conduit.

The method can include delivering a sealing gel through the fluidconduit, before delivering the fluid containing the therapeutic agent,to fill one or more voids that exist between the fluid conduit and thetissue. Tissue compressed into the first tissue-receiving space can forma seal that reduces proximal backflow of fluid ejected from the distalend of the fluid conduit beyond the tissue-receiving space. The methodcan include advancing a second outer sheath disposed over the firstouter sheath into the tissue such that tissue is compressed into asecond tissue-receiving space defined between an exterior surface of thefirst outer sheath and an interior surface of the distal end of thesecond outer sheath. The interior surface of the distal end of the firstouter sheath can be at least one of cylindrical, conical, convex, andconcave. The method can include controlling delivery of fluid throughthe fluid conduit based on an output of a microsensor embedded in thefluid conduit. The method can be used to treat at least one conditionselected from central-nervous-system (CNS) neoplasm, intractableepilepsy, Parkinson's disease, Huntington's disease, stroke, lysosomalstorage disease, chronic brain injury, Alzheimer's disease, amyotrophiclateral sclerosis, balance disorders, hearing disorders, and cavernousmalformations. Advancing the fluid conduit can include urging a noseportion into contact with tissue, the nose portion extending between thefirst outer sheath and a proximal catheter body such that the noseportion tapers from a reduced distal diameter corresponding to theoutside diameter of the first outer sheath to an enlarged proximaldiameter corresponding to the outside diameter of the catheter body. Thefluid conduit can be coupled to a distal end of a flexible catheter andthe method can include inserting the catheter through an incision,positioning the fluid conduit in proximity to the portion of the tissueusing stereotactic targeting, removing a stylet inserted through thecatheter, tunneling a proximal end of the catheter beneath the scalp ofthe patient, and coupling one or more proximal fluid connectors of thecatheter to a fluid delivery system.

The present invention further provides devices, systems, and methods asclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a perspective view of one exemplary embodiment of a CEDdevice;

FIG. 2 is a cross-sectional view of the device of FIG. 1, taken in aplane normal to the longitudinal axis of the device;

FIG. 3 is a schematic view of a fluid delivery system that includes thedevice of FIG. 1;

FIG. 4 is a schematic view of the device of FIG. 1 inserted into tissue;

FIG. 5 is a perspective view of another exemplary embodiment of a CEDdevice;

FIG. 6A is a plan view of another exemplary embodiment of a CED device;

FIG. 6B is a plan view of another exemplary embodiment of a CED device;

FIG. 6C is a plan view of another exemplary embodiment of a CED device;

FIG. 7 is a perspective view of another exemplary embodiment of a CEDdevice;

FIG. 8 is another perspective view of the CED device of FIG. 7;

FIG. 9 is a perspective view of the CED device of FIG. 7 with a depthstop and tip protector;

FIG. 10 is a plan view of the CED device of FIG. 7 with a length ofextension tubing;

FIG. 11 is a perspective view of a micro-tip of the CED device of FIG.7;

FIG. 12 is a perspective view of an exemplary embodiment of a moldingsystem;

FIG. 13 is a perspective view of the CED device of FIG. 7 beingmanufactured using the molding system of FIG. 12;

FIG. 14 is a top view of the CED device of FIG. 7 being manufacturedusing the molding system of FIG. 12;

FIG. 15 is another perspective view of the CED device of FIG. 7 beingmanufactured using the molding system of FIG. 12;

FIG. 16 is a partially-exploded sectional perspective view of anotherexemplary embodiment of a CED device;

FIG. 17 is a partially-exploded perspective view of the CED device ofFIG. 16;

FIG. 18 is a perspective view of the CED device of FIG. 16;

FIG. 19 is a map of mold filling time for the nose portion of the CEDdevice of FIG. 16;

FIG. 20 is a perspective view of an exemplary embodiment of a moldingsystem for forming the nose portion of the CED device of FIG. 16;

FIG. 21 is a scale drawing of an exemplary embodiment of the noseportion of the CED device of FIG. 16;

FIG. 22 is a series of images showing infusion of dye using a CED deviceinto a gel designed to simulate tissue;

FIG. 23 is another series of images showing infusion of dye using a CEDdevice into a gel designed to simulate tissue;

FIG. 24 is a magnetic resonance image of a pig brain in which a CEDdevice is inserted and a gadolinium dye is infused;

FIG. 25 is a series of magnetic resonance images showing infusion ofgadolinium into white matter of a pig's brain at flow rates of 1, 3, 5,10, and 20 μL/min using a CED device;

FIG. 26 is a series of magnetic resonance images showing infusion ofgadolinium into the thalamus of a pig's brain at flow rates of 1, 3, 5,10, and 20 μL/min using a CED device;

FIG. 27 is a series of magnetic resonance images showing infusion ofgadolinium into the putamen of a pig's brain at flow rates of 1, 2, 5,10, and 15 μL/min using a CED device;

FIG. 28 is a series of magnetic resonance images showing infusion ofgadolinium into the white matter of a pig's brain at a flow rate of 5μL/min using a CED device after infusion periods of 1, 9, 16, 24, and 50minutes;

FIG. 29 is a magnetic resonance image and an in vivo imaging systemimage of the thalamus of a pig's brain when a CED device is used tosimultaneously infuse galbumin and IVIS dye;

FIG. 30 is a comparison of infusate concentration using a CED device ofthe type described herein to simulated infusate concentration using atraditional catheter; and

FIG. 31 is a comparison of tissue expansion using a CED device of thetype described herein to simulated tissue expansion using a traditionalcatheter.

DETAILED DESCRIPTION

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the methods, systems, and devices disclosedherein. One or more examples of these embodiments are illustrated in theaccompanying drawings. Those skilled in the art will understand that themethods, systems, and devices specifically described herein andillustrated in the accompanying drawings are non-limiting exemplaryembodiments and that the scope of the present invention is definedsolely by the claims. The features illustrated or described inconnection with one exemplary embodiment may be combined with thefeatures of other embodiments. Such modifications and variations areintended to be included within the scope of the present invention.

Systems and methods are disclosed herein that generally involve CEDdevices with various features for reducing or preventing backflow. Insome embodiments, CED devices include a tissue-receiving space disposedproximal to a distal fluid outlet. Tissue can be compressed into orpinched/pinned by the tissue-receiving space as the device is insertedinto a target region of a patient, thereby forming a seal that reducesor prevents proximal backflow of fluid ejected from the outlet beyondthe tissue-receiving space. In some embodiments, CED devices include abullet-shaped nose proximal to a distal fluid outlet. The bullet-shapednose forms a good seal with surrounding tissue and helps reduce orprevent backflow of infused fluid.

FIG. 1 illustrates one exemplary embodiment of a CED device 10. Thedevice 10 generally includes a fluid conduit 12 and an outer sheath 14.The outer sheath 14 can be disposed coaxially over the fluid conduit 12such that the fluid conduit 12 extends out of a distal end 16 of theouter sheath 14. The fluid conduit 12 and the outer sheath 14 can besized and dimensioned such that a tissue-receiving space 18 is formedbetween an exterior surface of the fluid conduit 12 and an interiorsurface of the distal end 16 of the outer sheath 14.

The fluid conduit 12 can define one or more fluid lumens that extendgenerally parallel to the central longitudinal axis of the device 10.The fluid conduit 12 can include a fluid inlet port (not shown inFIG. 1) and a fluid outlet port 20. While a single fluid outlet port 20is shown in the illustrated embodiment, it will be appreciated that thedevice can include a plurality of fluid outlet ports, as well as aplurality of fluid inlet ports and a plurality of fluid lumens extendingtherebetween. The fluid inlet port can be positioned at a proximal endof the device 10, and can allow the fluid conduit 12 to be placed influid communication with a fluid reservoir, e.g., via one or morecatheters, pumps, meters, valves, or other suitable control devices.Such control devices can be used to regulate the pressure at which fluidis supplied to the device 10, or the rate or volume of fluid that issupplied to the device 10.

Fluid supplied to the conduit 12 though the fluid inlet port can bedirected through one or more inner lumens of the conduit 12 and releasedthrough the one or more fluid outlet ports 20. The fluid outlet ports 20can be sized, shaped, and/or positioned to control various releaseparameters of the fluid. For example, the fluid outlet ports 20 can beconfigured to control the direction in which fluid is released from thedevice 10, the distribution of the fluid within the target tissue, andthe velocity or pressure at which the fluid is released. In exemplaryembodiments, the size of the fluid outlet ports can progressivelyincrease towards the distal end of the device 10, which canadvantageously compensate for pressure loss that occurs along the lengthof the device such that fluid is released from each of the plurality offluid outlet ports at substantially the same pressure. The fluid outletports can also be positioned at various points around the circumferenceof the fluid conduit 12 or can be shaped to control the releasedirection of the fluid.

The fluid conduit 12 and/or the outer sheath 14 can have circularoutside cross-sections, which can advantageously allow the device 10 torotate within the tissue without causing trauma or forming large gapsbetween the exterior of the device and the surrounding tissue that mightincrease backflow. The fluid conduit 12 can also be flexible to allow itto move with the tissue in which it is inserted. While agenerally-cylindrical fluid conduit 12 is shown, the fluid conduit 12can also have a non-cylindrical or polygonal cross-section. For example,as described below with respect to FIG. 7, the fluid conduit 12 can be amicrofabricated tip that includes a substrate having a square orrectangular cross-section with one or more fluid channels disposedthereon. The interior of the outer sheath 14 can be shaped tosubstantially correspond to the cross-section of the fluid conduit 12.Alternatively, the outer sheath 14 can have an interior cross-sectionalshape that differs from the exterior cross-sectional shape of the fluidconduit 12. For example, the outer sheath 14 can have a substantiallycylindrical interior cross-sectional shape at its distal end, while thefluid conduit 12 can have a substantially square or rectangular exteriorcross-sectional shape, thereby defining the tissue-receiving space 18between the exterior of the fluid conduit 12 and the interior of theouter sheath 14.

As noted above, the outer sheath 14 can be disposed coaxially over thefluid conduit 12 such that the fluid conduit 12 extends out of thedistal end 16 of the outer sheath 14. A clearance space between theexterior surface of the fluid conduit 12 and the interior surface of thesheath 14 can define the tissue-receiving space 18. For example, asshown in FIG. 2, the fluid conduit 12 can have an outside diameter D1that is less than an inside diameter D2 of the outer sheath 14. Thedegree to which the diameter D2 exceeds the diameter D1 can dictate theamount of tissue that is compressed into or pinched by thetissue-receiving space 18.

In some embodiments, an adhesive or other filler can be disposed betweenthe fluid conduit 12 and the sheath 14 to hold the fluid conduit in afixed longitudinal position relative to the sheath and to maintain thefluid conduit in the center of the sheath (e.g., such that thetissue-receiving space 18 has a uniform width about the circumference ofthe fluid conduit). For example, the tissue-receiving space 18 canextend proximally a first distance from the distal end 16 of the sheath14, after which point the clearance space between the fluid conduit 12and the sheath 14 can be filled. In some embodiments, the sheath 14 canhave a stepped, tapered, or other similarly-shaped interior such that aclearance space exists along a distal portion of the sheath 14 and noclearance space exists along a proximal portion of the sheath 14.

In exemplary embodiments, the inside diameter of the distal end 16 ofthe outer sheath 14 can be about 1 μm to about 1000 μm, about 1 μm toabout 500 μm, about 1 μm to about 200 μm, or about 1 μm to about 20 μmgreater than the outside diameter of the fluid conduit 12. In exemplaryembodiments, the inside diameter of the distal end 16 of the outersheath 14 can be about 5 percent to about 500 percent, about 5 percentto about 250 percent, about 10 percent to about 100 percent, or about 10percent to about 20 percent greater than the outside diameter of thefluid conduit 12. In exemplary embodiments, the diameter D1 can be about50 μm to about 2000 μm, about 50 μm to about 1000 μm, or about 50 μm toabout 200 μm. In exemplary embodiments, diameter D2 can be about 51 μmto about 5000 μm, about 55 μm to about 1000 μm, or about 55 μm to about200 μm. The tissue-receiving space 18 can extend along the entire lengthof the outer sheath 14, or along only a portion of the outer sheath(e.g., along about 1 mm to about 100 mm, about 1 mm to about 50 mm, orabout 1 mm to about 10 mm of the distal-most portion of the outersheath).

The fluid conduit 12 and the outer sheath 14 can be formed from any of avariety of materials, including parylene compositions, silasticcompositions, polyurethane compositions, PTFE compositions, siliconecompositions, and so forth.

In some embodiments, the device 10 can be mounted on a support scaffold(not shown) to provide structural rigidity to the device and facilitateinsertion into the target tissue. Exemplary support scaffolds areillustrated and described in U.S. Publication No. 2013/0035560, filed onAug. 1, 2012, entitled “MULTI-DIRECTIONAL MICROFLUIDIC DRUG DELIVERYDEVICE,” the entire contents of which are incorporated herein byreference. To assist with tissue penetration and navigation, the distalend of the fluid conduit 12 and/or the distal end of the scaffold can betapered, pointed, and/or sharpened. In some embodiments, the fluidconduit 12 and/or the scaffold can be provided with a rounded atraumatictip so as to facilitate insertion through tissue without causing traumato the tissue. The support scaffold can be rigid or semi-rigid and canbe formed from a degradable thermoplastic polymer, for example, adegradable thermoplastic polyester or a degradable thermoplasticpolycarbonate. In some embodiments, the support scaffold can be formedfrom poly(lactic-co-glycolic acid) (PLGA) and can be configured tobiodegrade within the target tissue. This can advantageously eliminatethe need to remove the support scaffold once the device 10 is positionedwithin target tissue, thereby avoiding the potential to disrupt thepositioning of the fluid conduit 12. Any of a variety of other materialscan also be used to form the support scaffold, including silicon orvarious ceramics, metals, and plastics known in the art. The scaffoldcan have a width of approximately 100 μm to approximately 200 μm and canhave a length that varies depending on the target tissue (e.g.,depending on the depth at which the target tissue is situated). In oneembodiment, the scaffold is between 2 cm and 3 cm long. A variety oftechniques can be used to couple the fluid conduit 12 and/or the outersheath 14 to the support scaffold, such as surface tension from a waterdrop, adhesives, and/or a biocompatible petroleum jelly.

Any of the fluid conduit 12, the outer sheath 14, and/or the supportscaffold can contain or can be impregnated with a quantity of a drug.Alternatively, or in addition, a surface of these components can becoated with a drug. Exemplary drugs include anti-inflammatorycomponents, drug permeability-increasing components, delayed-releasecoatings, and the like. In some embodiments, one or more components ofthe device 10 can be coated or impregnated with a corticosteroid such asdexamethasone which can prevent swelling around the injection site anddisruptions to the fluid delivery pattern that can result from suchswelling.

The device 10 can also include one or more sensors 22 mounted in or onthe fluid conduit 12, the sheath 14, or the scaffold. The sensors 22 caninclude temperature sensors, pH sensors, pressure sensors, oxygensensors, tension sensors, interrogatable sensors, glutamate sensors, ionconcentration sensors, carbon dioxide sensors, lactate sensors,neurotransmitter sensors, or any of a variety of other sensor types, andcan provide feedback to a control circuit which can in turn regulate thedelivery of fluid through the device 10 based on one or more sensedparameters. One or more electrodes 24 can also be provided in or on thefluid conduit 12, the sheath 14, or the scaffold, which can be used todeliver electrical energy to target tissue, e.g., to stimulate thetarget tissue or to ablate the target tissue. In one embodiment,electrical energy is delivered through an electrode 24 while a drug issimultaneously delivered through the fluid conduit 12.

FIG. 3 is a schematic illustration of a drug delivery system 26 thatincludes the device 10. The system 26 includes a reservoir 28 of adrug-containing fluid that is coupled to a pump 30 via a control valve32. When the control valve 32 is opened, fluid in the reservoir 28 issupplied under pressure by the pump 30 to a pressure regulator 34, whichcan adjust a pressure at which the fluid is supplied to the device 10.The control valve 32, pump 30, and regulator 34 can be operativelycoupled to a controller 36 which can include a microprocessor and amemory and can be configured to execute a drug-delivery control programstored in a non-transitory computer-readable storage medium. Thecontroller 36 can be configured to open or close the valve 32, to turnthe pump 30 on or off, to change an output pressure of the pump 30,and/or to adjust a pressure set point of the regulator 34. Thecontroller 36 can also receive information indicative of a sensedparameter via a feedback loop that includes one or more sensors 22mounted in or on the device 10. Thus, in response to feedback from oneor more sensors 22 implanted with the device 10, the controller 36 canstart or stop the flow of fluid to the device 10, increase or decreasethe pressure at which fluid is supplied to the device 10, etc. In oneembodiment, the device 10 includes a pressure sensor 22 that measures afluid pressure in the vicinity of the device 10 and the controller 36 isconfigured to maintain the fluid supply pressure at a substantiallyconstant level based on feedback from the pressure sensor 22.

The device 10 can be used for CED of drugs to treat disorders of thebrain, spine, ears, neural tissue, or other parts of a human or animalbody. When used in the brain, the device 10 can circumvent theblood-brain barrier (BBB) by infusing drugs under positive pressuredirectly into tissue. The device 10 can provide a number of advantages,such as 1) a smaller cross-sectional area compared with conventionalneedles used in CED; 2) less disturbance to tissue when inserted intothe brain than conventional needles; 3) the reduction or elimination ofbackflow or reflux along the outside of the inserted part, which inturn, permits higher rates of drug delivery in the device 10 comparedwith conventional needles; 4) minimal or no occlusion of the fluiddelivery conduit 12 during insertion into the brain; 5) multiple lumenscan be provided through the fluid conduit 12, each conducting a distinctfluid (drug), which allows simultaneous, sequential, or programmeddelivery of multiple agents; 6) the device 10 has the potential to servesimultaneously as a drug delivery system and as a sensor-equipped probeto measure local tissue characteristics such as, but not limited to,pressure, pH, ion-specific concentrations, location, and otherparameters; and 7) the device 10 allows for directional control of thedrug release pattern.

In use, as described further below, the device 10 can be functionallyattached to the distal end of a long, thin insertion vehicle such as acannula or a needle in or on which a fluid attachment can be made to thefluid inlet port of the device's fluid conduit 12. This can beespecially advantageous in applications involving penetration ofrelatively thick tissue, e.g., insertion through a human skull.

In addition to delivering a drug-containing fluid, the device 10 canalso be used to deliver enzymes or other materials to modify tissuepermeability and improve drug distribution in the targeted tissue. Forexample, penetration of drug-containing nanoparticles into brain tissuecan be enhanced by enzymatic digestion of at least one brainextracellular matrix component and intracranial infusion of thenanoparticle into the brain tissue. In another embodiment, at least oneenzyme can be immobilized to a surface of the nanoparticle during thestep of enzymatic digestion. The device 10 can provide the ability todeliver enzymatic and/or other materials that can, e.g., modify the drugdelivery site, and therapeutic materials, in virtually any order,sequencing, and/or timing without the need to use different deliverydevices and the potential complications involved in doing so.

The device 10 can also be used to biopsy tissue, for example by passinga stylet or a grasping tool through the fluid conduit 12 to a targetsite and then withdrawing the stylet or grasping tool from the targetsite with a biopsy specimen therein. In some embodiments, the fluidconduit 12 can have a larger-diameter lumen extending therethrough forbiopsy purposes, with smaller fluid lumens formed therearound.

The device 10 can be used to deliver a drug-containing fluid underpositive pressure to a target tissue region. FIG. 4 illustrates anexemplary method for convection-enhanced delivery of a drug to targettissue 40 in a patient's brain. After appropriate site preparation andcleaning, a tissue opening can formed through the patient's scalp andskull to expose the brain tissue 40. Before or after forming the tissueopening, a pedestal can optionally be mounted to the patient to supportthe device 10 while it is inserted, which can be particularly useful inlong-term implantations.

The device 10 can optionally be coupled to a cannula (not shown) with amicrofabricated interface for mating with the device 10. Any of avariety of cannulas can be used, including standard cannulas configuredto mate to a stereotactic frame in guided surgery. In some embodiments,the cannula can include a flexible catheter suitable for extended (e.g.,30 day) implantation. The catheter can be about 15 cm long and about 2cm in diameter. The cannula can include a tubing portion that isapproximately 6 feet in length with connectors for fluid and biosensorinterface at the proximal end.

The device 10 can be advanced through the tissue opening and into thebrain tissue 40. As shown, the tissue-receiving space 18 can beconfigured to compress or pinch tissue received therein as the device 10is advanced through the tissue 40. Tissue compressed by thetissue-receiving space 18 can form a seal that reduces proximal backflowof fluid ejected from the outlet 20 of the fluid conduit 12 beyond thetissue-receiving space 18. In particular, as fluid ejected from theoutlet 20 of the fluid conduit 12 flows back proximally between theexterior surface of the fluid conduit 12 and the surrounding tissue 40,it encounters a shoulder of tissue 38 that is compressed into thetissue-receiving space 18. Compression of the tissue 38 against thewalls of the tissue-receiving space 18 forms a seal that resists flow ofthe fluid further in the proximal direction, thereby reducing orpreventing undesirable backflow of injected fluid away from the targetregion of the tissue.

As explained above, the device 10 can include a support scaffold tofacilitate penetration through the brain tissue towards the targetregion. One or more radiopaque markers can be included in the device 10to permit radiographic imaging (e.g., to confirm proper placement of thedevice 10 within or in proximity to the target tissue). In embodimentsin which a degradable scaffold is used, the scaffold can degrade shortlyafter insertion to leave behind only the fluid conduit 12 and outersheath 14. In some embodiments, the fluid conduit 12 and/or the sheath14 can be flexible to permit the device 10 to move with the brain tissue40 if the brain tissue 40 shifts within the skull. This canadvantageously prevent localized deformation of brain tissue adjacent tothe device 10 that might otherwise occur with a rigid device. Suchdeformation can lead to backflow of the pressurized fluid along thesurface of the device, undesirably preventing the fluid from reachingthe target tissue.

Once the device 10 is positioned within or adjacent to the targettissue, injected media (e.g., a drug-containing fluid) can be suppliedunder positive pressure to the device 10 through its fluid inletport(s). The injected media then flows through the fluid conduit 12 andis expelled under pressure from the outlet port(s) 20 in the targetregion of tissue. The delivery profile can be adjusted by varyingparameters such as outlet port size, outlet port shape, fluid conduitsize, fluid conduit shape, fluid supply pressure, fluid velocity, etc.In some embodiments, the device 10 can be configured to deliver fluid ata flow rate between about 5 μl per minute and about 20 μl per minute. Insome embodiments, the device 10 can be configured to deliver 50-100 μlper minute per channel, and each channel can be configured to supportgreater than 100 psi of pressure.

In some embodiments, prior to injecting the drug-containing fluid, a gelor other material can be injected through the device 10 to augment thetissue seal. For example, a sealing gel can be injected through thedevice 10 and allowed to flow back along the exterior of the device,filling and sealing any voids that may exist between the device and thesurrounding tissue, particularly within the tissue-receiving recess 18.Exemplary sealing materials include cyanoacrylate, protein glues, tissuesealants, coagulative glues (e.g., fibrin/thrombin/protein basedcoagulative glues), and materials such as those disclosed in U.S.Publication No. 2005/0277862, filed on Jun. 9, 2004, entitled “SPLITABLETIP CATHETER WITH BIORESORBABLE ADHESIVE,” the entire contents of whichare incorporated herein by reference.

It will be appreciated from the foregoing that the methods and devicesdisclosed herein can provide convection-enhanced delivery of functionalagents directly to target tissue within a patient with little or nobackflow. This convection-enhanced delivery can be used to treat a broadspectrum of diseases, conditions, traumas, ailments, etc. The term“drug” as used herein refers to any functional agent that can bedelivered to a human or animal patient, including hormones, stem cells,gene therapies, chemicals, compounds, small and large molecules, dyes,antibodies, viruses, therapeutic agents, etc.

In some embodiments, central-nervous-system (CNS) neoplasm can betreated by delivering an antibody (e.g., an anti-epidermal growth factor(EGF) receptor monoclonal antibody) or a nucleic acid construct (e.g.,ribonucleic acid interference (RNAi) agents, antisense oligonucleotide,or an adenovirus, adeno-associated viral vector, or other viral vectors)to affected tissue. Epilepsy can be treated by delivering ananti-convulsive agent to a target region within the brain. Parkinson'sdisease can be treated by delivering a protein such as glialcell-derived neurotrophic factor (GDNF) to the brain. Huntington'sdisease can be treated by delivering a nucleic acid construct such as aribonucleic acid interference (RNAi) agent or an antisenseoligonucleotide to the brain. Neurotrophin can be delivered to the brainunder positive pressure to treat stroke. A protein such as a lysosomalenzyme can be delivered to the brain to treat lysosomal storage disease.Alzheimer's disease can be treated by delivering anti-amyloids and/ornerve growth factor (NGF) under positive pressure to the brain.Amyotrophic lateral sclerosis can be treated by delivering a proteinsuch as brain-derived neurotrophic factor (BDNF) or ciliary neurotrophicfactor (CNTF) under positive pressure to the brain, spinal canal, orelsewhere in the central nervous system. Chronic brain injury can betreated by delivering a protein such as brain-derived neurotrophicfactor (BDNF) and/or fibroblast growth factor (FGF) under positivepressure to the brain.

It will be appreciated that use of the devices disclosed herein and thevarious associated treatment methods is not limited to the brain of apatient. Rather, these methods and devices can be used to deliver a drugto any portion of a patient's body, including the spine. By way offurther example, balance or hearing disorders can be treated byinjecting a drug-containing fluid directly into a portion of a patient'sear. Any of a variety of drugs can be used to treat the ear, includinghuman atonal gene. The methods and devices disclosed herein can also beused to deliver therapeutics (such as stem cells) to a fetus or to apatient in which the fetus is disposed. The methods and devicesdisclosed herein can be used to treat a cavernous malformation, forexample by delivering one or more antiangiogenesis factors thereto.

Any of the various treatments described herein can further includedelivering a cofactor to the target tissue, such as a corticosteroidimpregnated in the device, a corticosteroid coated onto the device,and/or a propagation enhancing enzyme. In addition, any of the varioustreatments described herein can further include long-term implantationof the device (e.g., for several hours or days) to facilitate long-termtreatments and therapies.

A number of variations on the device 10 are set forth below. Except asindicated, the structure and operation of these variations is identicalto that of the device 10, and thus a detailed description is omittedhere for the sake of brevity.

In some embodiments, the device 10 can include a plurality oftissue-receiving spaces 18. FIG. 5 illustrates an embodiment with afirst tissue-receiving space 18A and a second tissue-receiving space18B. As shown, a first outer sheath 14A is disposed over the fluidconduit 12 to define the first tissue-receiving space 18A. A secondouter sheath 14B is disposed over the first outer sheath 14A to definethe second tissue-receiving space 18B. Specifically, the secondtissue-receiving space 18B is formed between an exterior surface of thefirst outer sheath 14A and an interior surface of the distal end 16B ofthe second outer sheath 14B. While two tissue-receiving spaces areshown, it will be appreciated that any number of tissue-receiving spacescan be provided (e.g., three, four, five, or more) by adding additionalsheath layers. A single sheath layer can also be configured to providemultiple tissue-receiving spaces, for example by forming the sheathlayer with one or more stepped regions, each stepped region defining atissue-receiving space therein. Multi-stage devices such as that shownin FIG. 5 can provide additional sealing regions proximal to thedistal-most, primary sealing region. The provision of these secondary,tertiary, etc. sealing regions can augment the primary seal or act as abackup in case the primary seal is compromised.

As shown in FIGS. 6A-6C, the internal wall of the distal end 16 of theouter sheath 14 can be shaped to alter the dimensions of thetissue-receiving space 18 and the type of seal provided when tissue iscompressed therein. FIG. 6A illustrates a device 100 in which theinterior surface of the distal end 116 of the sheath 114 has a concavecurvature. FIG. 6B illustrates a device 200 in which the interiorsurface of the distal end 216 of the sheath 214 is conical. FIG. 6Cillustrates a device 300 in which the interior surface of the distal end316 of the sheath 314 has a convex curvature. These configurations canprovide for a sharper leading edge at the periphery of the sheath ascompared with the cylindrical tissue-receiving space 18 of the device10, and can increase the amount of tissue compressed into orpinched/pinned by the tissue-receiving space, as well as the degree ofcompression. A more-robust seal can thus be obtained in some instancesusing the configurations of FIGS. 6A-6C. It should be noted, however,that even in the case of a cylindrical tissue-receiving space, theleading edge of the sheath can be sharpened to deflect tissue into thetissue-receiving space and thereby form a better seal. The size andshape of the tissue-receiving space can be selected based on a varietyof parameters, including the type of tissue in which the device is to beinserted. In embodiments with a plurality of tissue-receiving spaces,each of the tissue receiving spaces can have the same configuration(e.g., all cylindrical, all conical, all convex, or all concave).Alternatively, one or more of the plurality of tissue-receiving spacescan have a different configuration. Thus, for example, one or moretissue-receiving spaces can be cylindrical while one or more othertissue receiving spaces are convex.

The tissue-receiving recesses of the devices disclosed herein caninclude various surface features or treatments to enhance the sealformed between the device and the surrounding tissue or gel. Forexample, the tissue-receiving recesses can be coated with abiocompatible adhesive or can have a textured surface to form a tighterseal with the tissue or gel.

FIG. 7 illustrates an exemplary embodiment of a CED device 400 thatgenerally includes a fluid conduit in the form of a micro-tip 412 and anouter sheath 414. The micro-tip 412 includes a substrate 442, which canbe formed from a variety of materials, including silicon. The substrate442 can have any of a variety of cross-sectional shapes, including asquare or rectangular cross-section as shown. One or more fluid channels444 can be formed on the substrate 442. The fluid channels 444 can beformed from a variety of materials, including parylene. Additionaldetails on the structure, operation, and manufacture of microfabricatedtips such as that shown in FIG. 7 can be found in U.S. Publication No.2013/0035560, filed on Aug. 1, 2012, entitled “MULTI-DIRECTIONALMICROFLUIDIC DRUG DELIVERY DEVICE,” the entire contents of which areincorporated herein by reference.

The outer sheath 414 can be disposed coaxially over the micro-tip 412 soas to form a tissue-receiving space 418 therebetween. In someembodiments, the micro-tip 412 can have a substantially rectangularexterior cross-section and the outer sheath 414 can have a substantiallycylindrical interior cross-section. In other embodiments, the micro-tip412 and the outer sheath 414 can have corresponding cross-sectionalshapes with a clearance space defined therebetween. The proximal end ofthe outer sheath 414 can be coupled to a catheter 446. The catheter 446can be rigid or flexible, or can include rigid portions and flexibleportions. A nose portion 448 (sometimes referred to herein as a “bulletnose” or a “bullet nose portion”) can be disposed between the outersheath 414 and the catheter 446, or can be disposed over a junctionbetween the outer sheath 414 and the catheter 446. As shown, the noseportion 448 can taper from a reduced distal diameter corresponding tothe outside diameter of the sheath 414 to an enlarged proximal diametercorresponding to the outside diameter of the catheter 446. The taperedtransition provided by the nose portion 448 can advantageously providestress-relief as it can act as a smooth transition from the sheath 414to the catheter body 446, avoiding any uneven stresses on thesurrounding tissue that may create paths for fluid backflow. The noseportion 448 can be conically tapered, as shown, or can taper along aconvex or concave curve. Various compound shapes can also be used thatinclude conical portions, convex portions, and/or concave portions. Thenose portion 448 can also be replaced with a blunt shoulder that extendsperpendicular to the longitudinal axis of the device 400. Any of avariety of taper angles can be used for the nose portion 448. Forexample the nose portion 448 can taper at an angle in a range of about10 degrees to about 90 degrees relative to the longitudinal axis of thedevice 400, in a range of about 20 degrees to about 70 degrees relativeto the longitudinal axis of the device, and/or in a range of about 30degrees to about 50 degrees relative to the longitudinal axis of thedevice. For example, the nose portion 446 can taper at an angle ofapproximately 33 degrees relative to the longitudinal axis of the device400. In some embodiments, additional sheaths can be provided, e.g., asdescribed above with respect to FIG. 5.

As shown in FIG. 8, the catheter 446 can include length markings orgraduations 450 to indicate the insertion depth of the device 400. Insome embodiments, the catheter 446 can be a straight rigid cathetersized and configured for acute stereotactic targeting. The catheter 446can be formed from any of a variety of materials, including flexiblematerials, rigid materials, ceramics, plastics, polymeric materials,PEEK, polyurethane, etc. and combinations thereof. In an exemplaryembodiment, the catheter 446 has length of about 10 cm to about 40 cm,e.g., about 25 cm. The catheter 446 can include one or more fluid linesextending therethrough. The fluid lines can be defined by the catheterbody itself or can be defined by one or more inner sleeves or liningsdisposed within the catheter body. Any of a variety of materials can beused to form the inner sleeves or linings, such as flexible materials,rigid materials, polyimide, pebax, PEEK, polyurethane, silicone, fusedsilica tubing, etc. and combinations thereof.

As shown in FIG. 9, one or more standard Luer or other connectors 452can be coupled to the proximal end of the catheter 446 to facilitateconnection with a fluid delivery system of the type shown in FIG. 3. Inthe illustrated embodiment, the system 400 includes two connectors 452,one for each of the two fluid channels formed in the catheter 446 andthe micro-tip 412. It will be appreciated, however, that any number offluid channels and corresponding proximal catheter connectors can beprovided. The system 400 can also include a collar 454 disposed over thecatheter 446 to act as a depth stop for setting the desired insertiondepth and preventing over-insertion. The collar 454 can belongitudinally slidable with respect to the catheter 446 and can includea thumb screw 456 for engaging the catheter to secure the collar in afixed longitudinal position with respect thereto. The system 400 canalso include a tip protector 458 for preventing damage to the micro-tip412 during insertion into stereotactic frame fixtures. Exemplary tipprotectors are disclosed in U.S. Provisional Application No. 61/835,905,filed on Jun. 17, 2013, entitled “METHODS AND DEVICES FOR PROTECTINGCATHETER TIPS,” the entire contents of which are incorporated herein byreference.

As shown in FIG. 10, the system 400 can include a length of extensiontubing 460 to provide a fluid pathway between the proximal connectors452 of the catheter 446 and a fluid delivery system of the type shown inFIG. 3. In the illustrated embodiment, dual-channel peel-away extensionlines 460 are shown. In an exemplary method of using the system 400, anincision can be formed in a patient and the catheter 446 can be insertedthrough the incision and implanted in a target region of tissue (e.g., aregion of the patient's brain or central nervous system). The catheter446 can be left in the target region for minutes, hours, days, weeks,months, etc. In the case of a flexible catheter 446, the proximal end ofthe catheter can be tunneled under the patient's scalp with the proximalconnectors 452 extending out from the incision. The catheter 446 can beinserted through a sheath to keep the catheter stiff and straight forstereotactic targeting. Alternatively, or in addition, a stylet can beinserted through the catheter to keep the catheter stiff and straightfor stereotactic targeting. In some embodiments, the stylet can beinserted through an auxiliary lumen formed in the catheter such that theprimary fluid delivery lumen(s) can be primed with fluid during catheterinsertion. Thus, in the case of a catheter with first and second fluidlumens, a third lumen can be included for receiving the stylet.

FIG. 11 is a close-up view of the exemplary micro-tip 412. As shown, themicro-tip 412 generally includes a central body portion 462 with firstand second legs or tails 464 extending proximally therefrom and a tipportion 466 extending distally therefrom. First and second microfluidicchannels 444 are formed in or on the micro-tip 412 such that they extendalong the proximal legs 464, across the central body portion 462, anddown the distal tip portion 466. The channels 444 can each include oneor more fluid inlet ports (e.g., at the proximal end) and one or morefluid outlet ports (e.g., at the distal end). As noted above, additionaldetails on the structure, operation, and manufacture of microfabricatedtips such as that shown in FIG. 11 can be found in U.S. Publication No.2013/0035560, filed on Aug. 1, 2012, entitled “MULTI-DIRECTIONALMICROFLUIDIC DRUG DELIVERY DEVICE,” the entire contents of which areincorporated herein by reference.

Systems and methods for manufacturing and/or assembling the CED device400 are shown in FIGS. 12-15. Generally speaking, after the micro-tip412 is fabricated, it can be positioned in a molding or casting systemto couple the one or more sheaths 414 to the micro-tip, to form the noseportion 448, and/or to couple fluid lines in the catheter 446 to thefluid channels 444 of the micro-tip.

FIG. 12 illustrates an exemplary embodiment of a molding system 500. Thesystem 500 includes a base plate 502 with a cradle 504 in which aproximal portion of the catheter 446 is supported. Upper and lower moldblocks 506, 508 are coupled to the base plate 502 by a clamping block510 with one or more screws 512. The screws 512 can be tightened to lockthe mold blocks 506, 508 in position during an injection process and canbe removed to allow the mold blocks to be opened for insertion orremoval of the CED device components. The system 500 also includes aninlet port 514 through which flowable material can be injected, pumped,etc. into the mold.

As shown in FIGS. 13-15, the lower mold block 508 includes a recess inwhich the lower half of the catheter body 446 can be disposed and arecess in which the lower half of the sheath 414 can be disposed. A moldcavity 516 which is substantially a negative of the lower half of thenose portion 448 is formed between the recesses. The recesses can besized such that the catheter body 446 and the sheath 414 form a sealwith the mold block 508 to prevent flowable material injected into themold cavity 516 from escaping. One or more injection ports or channels514 are formed in the mold block 508 to allow flowable material to beinjected into the cavity 516. While not shown, it will be appreciatedthat the upper mold block 506 is configured in a similar manner to thelower mold block 508, with recesses that can receive the upper halves ofthe catheter body 446 and the sheath 414 and a mold cavity 516 which issubstantially a negative of the upper half of the nose portion 448.

In use, the micro-tip 412 is positioned such that the proximal legs 464are disposed within respective fluid lines formed in the catheter body446 and such that the distal tip portion 466 of the micro-tip ispositioned within the inner lumen of the sheath 414. As noted above, insome embodiments, the catheter fluid lines can be formed by innerlinings (e.g., fused silica tubes) encased in an outer housing (e.g., aceramic housing) that defines the catheter body 446. The inner liningscan prevent leaks and hold the catheter body 446 together in the eventthat the outer housing is cracked or damaged. The micro-tip 412,catheter body 446, and sheath 414 are sandwiched between the upper andlower mold blocks 506, 508 and a flowable material is injected throughthe mold channels 514 to form the nose portion 448 within the moldcavity 516, and to couple the fluid lines in the catheter 446 to thefluid channels 444 of the micro-tip. Exemplary flowable materialsinclude UV resins, polymers such as polyurethanes, acrylics, PTFE,ePTFE, polyesters, and so forth.

The flowable material can be injected at low rates to fill the cavity516. In embodiments in which UV resin is used, the upper and lower moldblocks 506, 508 can be made of a clear material to allow UV light tocure the UV resin. As the UV resin is injected into the micro-moldcavity 516, it can start to wick/flow up over the micro-tip tails 464and under the fluid lines that sit over the tails. Once the resin flowsinto the fluid lines, it can be flashed with UV light to “freeze” it inplace and avoid wicking/flowing too much (and not completelyencapsulating the tails 464 and the inlet holes on the tips of thetails). After the material cures, the mold blocks 506, 508 can beseparated and the CED device 400 can be removed from the molding system500.

It will be appreciated that the above systems and methods can be variedin a number of ways without departing from the scope of the presentdisclosure. For example, the molding process can be used only forcoupling the fluid lines, and the bullet nose portion can be formedusing a different process once the fluid connections are made. Also,while wicking is described herein as the mechanism by which the fluidline bonds are formed, it will be appreciated that these bonds can alsobe controlled by fill pressure, timing, and other molding variables. Thebullet nose can be over-molded directly onto the micro-tip. While anexemplary micro-tip and an exemplary catheter body are shown, it will beappreciated that the micro-molding methods and devices disclosed hereincan be used with any of a variety of tips and/or catheters.

Alternative systems and methods for manufacturing and/or assembling theCED device 400 are shown in FIGS. 16-21. As shown in FIGS. 16-19, thebullet nose and the one or more sheaths or over tubes can be assembledseparately using an over-molding process as described below to create amolded part 470. To assemble the system 400, the proximal legs 464 ofthe micro-tip 412 are inserted into the distal end of the catheter body446 (e.g., by inserting each leg into a respective lining disposedwithin an outer catheter housing). A flowable material (e.g., anadhesive such as a UV curable adhesive) can then be applied to the legs464 to bond the fluid channels on each leg to a corresponding fluid lineof the catheter body 446. The molded part 470 can then be slid over thedistal end of the micro-tip 412 such that the central body portion 462of the micro-tip is disposed in a hollow interior of the molded part andsuch that the tip portion 466 of the micro-tip extends through themolded part and protrudes from the distal end thereof.

The molded part 470 can include a shoulder that defines a proximal maleportion 472 that mates into a female counterbore 474 formed in thedistal tip of the catheter body 446. Alternatively, the catheter body446 can define a male portion and the molded part 470 can include afemale counterbore. It will also be appreciated that other ways ofmating the catheter body 446 to the molded part 470 can be used, such asa threaded interface, a snap-fit interface, a key and slot interface, orany other interlocking interface that provides alignment and/or overlapbetween the molded part and the catheter body. In some embodiments, thecounterbore 474 can be formed by machining a recess into the distal endof a ceramic catheter body 446. The inner linings of the catheter canthen be inserted into the ceramic outer housing such that the terminalends of the inner linings are flush with the floor of the counterbore474. The molded part 470 can be attached to the catheter body 446 usinga flowable material (e.g., a UV adhesive), which can be applied to thecounterbore 474 and/or the male portion 472 prior to assembling thecomponents or which can be applied through one or more openings 476formed in the sidewall of the molded part after the components areassembled or dry fit. The flowable material is allowed to cure to form aseal between the fluid lines and to secure the components of the CEDdevice 400 to one another.

An exemplary over-molding system 600 for forming the bullet nose andcoupling the bullet nose to one or more over-tubes to form the moldedpart 470 is shown in FIG. 20. The molding system 600 includes upper andlower plates 602, 604 that sandwich the one or more over-tubes andtogether define a negative of the bullet nose. The plates 602, 604 alsodefine a plug for forming the bullet nose as a hollow structure whichcan later be filled as described above during final assembly. A flowablematerial can be injected through injection ports 606 formed in theplates 602, 604 using a syringe or pump to form the hollow bullet noseover the one or more over-tubes. In some embodiments, the flowablematerial is a hot resin injected under pressure which forms a stronghold with the over-tube upon curing. The over-tube can be formed fromany of a variety of materials, including fused silica tubing.

A scale drawing of an exemplary molded part 470 is shown withrepresentative dimensions in FIG. 21. Any of the nose portions and/orsheaths described herein can be formed to the same or similar externaldimensions. Unless otherwise indicated, the dimensions shown in FIG. 21are specified in inches.

FIGS. 22-23 illustrate exemplary results of a gel study conducted byinfusing dye through a CED device of the type described herein havingfirst and second fluid channels into a gel designed to simulate tissue.As shown in FIG. 22, little or no backflow occurs at flowrates of 5, 10,and 12 μL/min (total flowrate of both channels combined). As shown inFIG. 23, a flowrate of 5 μL/min resulted in a uniform distribution ofthe dye over time with little or no backflow.

FIGS. 24-29 illustrate exemplary results of an animal study conductedusing an in-vivo pig model in which multiple anatomies were infusedusing CED devices of the type described herein. Little or no backflowalong the catheter track was observed at flow rates which are muchhigher than typical clinical flow rates for CED. The study demonstratedthe capability to infuse small, medium, and large molecules using CEDdevices of the type disclosed herein, and confirmed the functionality ofindependent flow channels. No blockages or introduction of air bubblesoccurred during a multi-hour acute infusion. The device was found to becompatible with magnetic resonance imaging and other stereotacticsurgical procedures. No leaks, bond breakages, or other catheter issueswere observed.

As shown in FIG. 24, when inserted into a pig brain, the ceramiccatheter body and the bullet nose appear as a thick black line in amagnetic resonance (MR) image. Infused gadolinium (Gd) appears as abright cloud in the MR image. The micro-tip is not readily visible inthe MR image due to its small size.

FIG. 25 illustrates a series of MR images showing infusion of gadoliniuminto white matter of a pig's brain at flow rates of 1, 3, 5, 10, and 20μL/min. As shown, no backflow of infusate occurs along the ceramiccatheter shaft track. When the infusion cloud becomes too large, theinfusate overflows into surrounding anatomy, rather than flowing backalong the catheter track, highlighting the capability for the system toreduce or prevent backflow. While flow rates of up to 20 μL/min areshown, it is expected that similar results would be obtained for flowrates of 30 μL/min or more. These higher flow rates could not be testedduring the animal study because the subject brain(s) became saturatedwith gadolinium.

FIG. 26 illustrates a series of MR images showing infusion of gadoliniuminto the thalamus of a pig's brain at flow rates of 1, 3, 5, 10, and 20μL/min. As shown, no backflow of infusate occurs along the ceramiccatheter shaft track. While there is slight backflow across the bulletnose at approximately 20 μL/min, this is a flowrate that issignificantly higher than typical clinical CED flowrates (generallyabout 5 μL/min).

FIG. 27 illustrates a series of MR images showing infusion of gadoliniuminto the putamen of a pig's brain at flow rates of 1, 2, 5, 10, and 15μL/min. As shown, no backflow of infusate occurs along the ceramiccatheter shaft track as the infusate stays spherical throughout theramped infusion.

The above-described backflow study showed that there is minimal backflowalong the catheter shaft at high flow rates (up to 20 μL/min for whitematter, 5-20 μL/min for the thalamus, and 5-15 μL/min for the putamen).These flow rates are much higher than typical clinical CED flow rates(e.g., about 5 μL/min). The determination as to whether backflowoccurred was made using a 3D analysis of the infusion, not solely basedon the MR images included herein. In a total of eleven infusionsconducted in various anatomies, zero incidences of backflow wereobserved.

FIG. 28 illustrates a series of MR images showing infusion of gadoliniuminto the white matter of a pig's brain at a flow rate of 5 μL/min afterinfusion periods of 1, 9, 16, 24, and 50 minutes. The lower set ofimages includes a distribution overlay. As shown, a uniform distributionwith no backflow is observed even for long-duration infusions and when alarge volume of infusate is delivered. Similar results were observed ininfusions into the thalamus and putamen of the pig's brain.

FIG. 29 illustrates an MR image and an in vivo imaging system (IVIS)image of the thalamus of a pig's brain when a CED device of the typedescribed herein is used to simultaneously infuse galbumin(gadolinium-labeled albumin laced with europium) through a first fluidchannel and IVIS dye through a second fluid channel. As shown, the twodifferent infusates were successfully infused from the two independentchannels. A uniform distribution of the two infusates indicates mixingat the tip outlet as desired. No evidence of subarachnoid leakage wasobserved. This demonstrates that the system can be used to deliver Gdtracer and a drug or other molecule while monitoring the Gd tracer underMR to monitor the distribution of the drug or other molecule.

FIGS. 30-31 illustrate comparisons between measurements taken with CEDdevices of the type described herein and simulated measurements for atraditional 0.3 mm catheter. As shown in FIG. 30, CED devices of thetype described herein achieve a more uniform concentration of infusedcolloidal Gd in white matter than traditional 0.3 mm catheters. As shownin FIG. 31, when using CED devices of the type described herein,extracellular expansion of white matter tissue is confined to the tiparea by the bullet nose and tube-step, which prevents backflow along thecatheter track. With traditional 0.3 mm catheters, on the other hand,increased extracellular expansion occurs along the catheter track due tothe infusion pressure and backflow results.

The above-described infusion studies showed that 150 μL of infusatecould be delivered into white matter and thalamus with no backflow alongthe catheter track. It also showed that the concentration profile ofinfusate distribution in tissue was within typical ranges forintraparenchymal drug delivery. Successful colloidal Gd (large molecule30-50 nm) infusion was also demonstrated.

The devices disclosed herein can be manufactured using any of a varietyof techniques. For example, the devices can be manufactured byassembling lengths of tubing over one another, by micro-machininglengths of tubing, by molding steps or nose features containingtissue-receiving spaces onto a fluid conduit, or by constructing one ormore portions of the device on a substrate using a lithographicmicrofabrication process.

Further details on CED methods and devices, as well as relatedmanufacturing techniques, exemplary micro-tips, and exemplary cathetersare disclosed in the following references, the entire contents of eachof which are hereby incorporated by reference herein:

U.S. Publication No. 2013/0035560, filed on Aug. 1, 2012, entitledMULTI-DIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICE;

U.S. Publication No. 2013/0035574, filed on Aug. 1, 2012, entitledMICROFLUIDIC DRUG DELIVERY DEVICES WITH VENTURI EFFECT;

U.S. Publication No. 2013/0035660, filed on Aug. 1, 2012, entitledMULTIDIRECTIONAL MICROFLUIDIC DRUG DELIVERY DEVICES WITH CONFORMABLEBALLOONS;

U.S. Provisional Application No. 61/835,905, filed on Jun. 17, 2013,entitled METHODS AND DEVICES FOR PROTECTING CATHETER TIPS;

U.S. Provisional Application No. 61/860,402, filed on Jul. 31, 2013,entitled DRUG DELIVERY SYSTEMS;

U.S. Publication No. 2010/0098767, filed on Jul. 31, 2009, entitledCONVECTION ENHANCED DELIVERY APPARATUS, METHOD, AND APPLICATION; and

U.S. Publication No. 2013/0046230, filed on Nov. 7, 2012, entitledULTRASOUND-ASSISTED CONVECTION ENHANCED DELIVERY OF COMPOUNDS IN VIVOWITH A TRANSDUCER CANNULA ASSEMBLY.

Although the invention has been described by reference to specificembodiments, it should be understood that numerous changes may be madewithin the spirit and scope of the inventive concepts described.Accordingly, it is intended that the invention not be limited to thedescribed embodiments, but that it have the full scope defined by thelanguage of the following claims.

What is claimed is:
 1. A method of delivering a therapeutic agent to apatient, comprising: advancing a fluid conduit having a first outersheath disposed therearound into tissue to compress tissue into a firsttissue-receiving space defined between an exterior surface of the fluidconduit and an interior surface of a distal end of the first outersheath and to urge a nose portion disposed at a location proximal to thefirst tissue-receiving space into contact with the tissue the noseportion tapering from a reduced distal diameter corresponding to anoutside diameter of the first outer sheath to an enlarged proximaldiameter corresponding to an outside diameter of a catheter; anddelivering fluid containing the therapeutic agent under positivepressure through the catheter, through the fluid conduit, and into aportion of the tissue adjacent to a distal end of the fluid conduit. 2.The method of claim 1, further comprising delivering a sealing gelthrough the fluid conduit, before delivering the fluid containing thetherapeutic agent, to fill one or more voids that exist between thefluid conduit and the tissue.
 3. The method of claim 1, wherein tissuecompressed into the first tissue-receiving space forms a seal thatreduces proximal backflow of fluid ejected from the distal end of thefluid conduit beyond the tissue-receiving space.
 4. The method of claim1, wherein the interior surface of the distal end of the first outersheath is at least one of conical, convex, and concave.
 5. The method ofclaim 1, further comprising controlling delivery of fluid through thefluid conduit based on an output of a microsensor embedded in the fluidconduit.
 6. The method of claim 1, wherein the method is used to treatat least one condition selected from central-nervous-system (CNS)neoplasm, intractable epilepsy, Parkinson's disease, Huntington'sdisease, stroke, lysosomal storage disease, chronic brain injury,Alzheimer's disease, amyotrophic lateral sclerosis, balance disorders,hearing disorders, and cavernous malformations.
 7. The method of claim1, wherein the first tissue-receiving space is defined between asubstantially rectangular exterior cross-section of the first fluidconduit and a substantially cylindrical interior cross-section of thefirst outer sheath.
 8. The method of claim 1, wherein the fluid conduitincludes a substrate having one or more fluid channels formed on anouter surface of the substrate.
 9. The method of claim 8, wherein thesubstrate has a rectangular exterior cross-section.
 10. The method ofclaim 8, wherein the substrate is formed from silicon.